Phase 1B Study of Tirabrutinib in Combination with Idelalisib Or Entospletinib in Previously Treated B-Cell Lymphoma

Leukemia https://doi.org/10.1038/s41375-020-01108-x

LETTER

Lymphoma Phase 1b study of tirabrutinib in combination with idelalisib or entospletinib in previously treated B-cell lymphoma

1 2 2 3 4 Franck Morschhauser ● Martin J. S. Dyer ● Harriet S. Walter ● Alexey V. Danilov ● Loic Ysebaert ● 5 6 7 8 9 Daniel James Hodson ● Christopher Fegan ● Simon A. Rule ● John Radford ● Guillaume Cartron ● 10 11 12 13 Krimo Bouabdallah ● Andrew John Davies ● Stephen Spurgeon ● Nishanthan Rajakumaraswamy ● 13 13 13 13 13 14 Biao Li ● Rita Humeniuk ● Xi Huang ● Pankaj Bhargava ● Juliane M. Jürgensmeier ● Gilles Salles

Received: 17 July 2020 / Revised: 17 November 2020 / Accepted: 30 November 2020 © The Author(s) 2020. This article is published with open access

To the Editor: ibrutinib, which is characterized by high-affinity inhibition of ten kinases other than BTK [8]. In two separate phase B-cell receptor (BCR) signaling pathway inhibitors 1 studies, TIRA was evaluated for treatment of patients with (including Bruton’s tyrosine kinase [BTK] inhibitors, and follicular lymphoma (FL), non-germinal center B-cell (non- phosphatidylinositol-3 kinase inhibitors [PI3Ki]) have GCB) diffuse large B-cell lymphoma (DLBCL), mantle cell 1234567890();,: 1234567890();,: shown clinical efficacy in non-Hodgkin lymphoma (NHL). lymphoma (MCL), and lymphoplasmacytic lymphoma However, responses to these agents have been limited in (LPL) [7, 9]. Response rates were 20–100% across disease depth and duration. This may be due to resistance to PI3Kδ types, with a favorable safety profile [7, 9]. The only car- and BTK inhibitors as monotherapy [1–5]. The emergence diovascular adverse events (AEs) were atrial fibrillation/ of resistant clones may be addressed by combining these 2 flutter, which occurred in 5 of the 107 patients in the classes of drugs. Furthermore, tolerability of these drug 2 studies, 4 of whom had this as a pre-existing medical classes has been a concern. Combination therapy using condition. lower doses of one or more classes of inhibitors may We assessed the combination of TIRA with a PI3Kδ address some limitations. inhibitor (idelalisib [IDELA]) or a SYK inhibitor (entos- Tirabrutinib (TIRA, formerly ONO/GS-4059) is a pletinib [ENTO]). IDELA is a first-in-class PI3Kδ inhibitor selective, irreversible, and small-molecule BTK inhibitor approved for the treatment of relapsed or refractory (R/R) [6, 7]. TIRA has greater target selectivity compared with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and FL in the US and Europe [10]. Response rates were 54% and 58% in FL and SLL, Supplementary information The online version of this article (https:// respectively [10]. ENTO (formerly GS-9973) is an inves- doi.org/10.1038/s41375-020-01108-x) contains supplementary tigational selective noncovalent inhibitor of SYK. In a material, which is available to authorized users.

* Franck Morschhauser 8 University of Manchester and The Christie NHS Foundation Trust, [email protected] Manchester, UK 1 Univ. Lille, CHU Lille, ULR 7365, GRITA - Groupe de 9 Department of Clinical Hematology, University Hospital of Recherche sur les formes Injectables et les Technologies Montpellier and UMR-CNRS 5535, Montpellier, France Associées, F-59000 Lille, France 10 Hematology Clinic, University Hospital of Bordeaux, 2 Ernest and Helen Scott Haematological Research Institute, Pessac, France University of Leicester, Leicester, UK 11 Cancer Research UK Centre, University of Southampton, 3 City of Hope National Medical Center, Duarte, CA, USA Southampton, UK 4 Département d’Hématologie IUCT-Oncopole, Toulouse, France 12 Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA 5 WT-MRC Stem Cell Institute, University of Cambridge, Cambridge, UK 13 Gilead Sciences, Inc, Foster City, CA, USA 6 University Hospital of Wales, Cardiff, UK 14 Hospices Civils de Lyon, Department of Hematology, Université de Lyon, Lyon, France 7 University of Plymouth Medical School, Plymouth, UK F. Morschhauser et al. study of patients with FL, LPL, MCL, and marginal zone patients having achieved a response (27% complete, lymphoma (MZL), treatment with ENTO 800 mg twice 38% partial) on their last prior therapy. daily resulted in response rates ranging from 12% to 35%, Study drug exposures are shown in Supplementary Fig. 2 with manageable toxicity [11]. and Supplementary Table 3. In the TIRA/IDELA and The present study was designed to evaluate the safety of TIRA/ENTO groups, discontinuations due to AEs occurred TIRA/IDELA and TIRA/ENTO combinations and define in 10% and 3% of patients, and discontinuations due to PD the maximum tolerated dose (MTD) for each combination occurred in 60% and 48% of patients, respectively. Five and preliminary efficacy in patients with selected subtypes patients on TIRA/IDELA and 6 patients on TIRA/ENTO of NHL and CLL. The results from CLL patients have been died on-study, all due to PD. reported elsewhere [12]. Herein, we report results in NHL In the TIRA/IDELA treatment group, treatment- patients. emergent AEs (TEAEs) occurred in 100% of patients, This was a phase 1b, open-label, multicenter, sequential with 38% having serious TEAEs (Table 2). TEAEs leading dose-escalation and -expansion study in patients with R/R to investigator-determined TIRA discontinuation occurred NHL (NCT02457598). Eligible patients had a diagnosis of in 15% of TIRA/IDELA patients. These included anemia, non-GCB DLBCL, FL, MCL, or other indolent NHL neutropenia, pancytopenia, atrial fibrillation, and transami- (MZL, SLL, or LPL) as documented by medical records. nase increased (1 patient each), and rash (n = 2). TEAEs Patients had a history of ≥1 prior therapy (but no prior leading to discontinuation of IDELA occurred in 18% of exposure to BTK or PI3K inhibitors), were not transplant patients. Grade ≥3 laboratory abnormalities occurred in 69% eligible, and had either progressive disease (PD) or no of TIRA/IDELA patients. The most common hematologic response (stable disease) on their most recent treatment and hepatic abnormalities (excluding lymphopenia) were regimen. Except for those with LPL, patients had a radi- decreased neutrophils and platelets, and increased liver ologically measurable presence of ≥1 lymph node lesions. enzymes (Supplementary Table 4). One MZL patient Patients were treated with TIRA ranging from 20 mg to receiving TIRA 20 mg BID + IDELA 50 mg BID experi- 160 mg QD in combination with IDELA (50 mg BID or enced a dose-limiting toxicity (grade 4 neutropenia and 100 mg QD) or ENTO (200 mg QD or 400 mg QD) grade 4 thrombocytopenia), and subsequently the protocol according to a standard 3 + 3 dose-escalation schema was amended to include only TIRA QD dosing. MTD with (Supplementary Table 1). TIRA QD dosing in combination with IDELA was not The primary endpoint was safety, evaluated by the reached. occurrence of AEs, and laboratory abnormalities defined as In the TIRA/ENTO treatment group, TEAEs occurred in dose-limiting toxicities (Supplementary Table 2). Pre- 95% of patients, with 36% having serious TEAEs (Table 2). liminary efficacy was evaluated by overall response rate TEAEs leading to investigator-determined TIRA dis- (ORR). Secondary endpoints included pharmacokinetic continuation occurred in 3% of TIRA/ENTO patients. (PK) parameters, progression-free survival (PFS), duration These included biphasic mesothelioma, lung neoplasm of response, time to response, and proportion of patients (malignant), and pancreatitis (one patient each). TEAEs achieving both complete response and undetectable minimal leading to discontinuation of ENTO occurred in 8% of residual disease (MRD). Patients had CT or MRI scans patients. Grade ≥3 laboratory abnormalities occurred in 57% every 12 weeks; those with DLBCL had an additional scan of TIRA/ENTO patients. The most common hematologic at week 6. Further details on study methods are provided in and hepatic abnormalities (excluding lymphopenia) were the Supplementary Methods. decreased neutrophils and platelets, and increased liver Overall, 40 patients were treated with TIRA/IDELA and enzymes (Supplementary Table 4). There were no dose- 91 with TIRA/ENTO (Supplementary Fig. 1). Patient limiting toxicities in the TIRA/ENTO group and MTD was characteristics and baseline demographics of the NHL not reached. subtypes included in this study are shown in Table 1. Forty- Efficacy results are reported across all dose groups in seven percent of DLBCL patients in the TIRA/IDELA both combinations. Response rates are shown in Supple- group were refractory to their last prior regimen; 67% were mentary Table 5. In DLBCL patients, response rates were refractory to prior regimens in the TIRA/ENTO group. In comparable across both combinations; the ORR was 24% the TIRA/IDELA group, 70% of FL patients had failed ≥2 with TIRA/IDELA and 26% with TIRA/ENTO. The ORR prior therapies, and 50% had failed both rituximab/anti- in patients with FL was 20% with TIRA/IDELA and 35% CD20+ and alkylating regimens. Eighty percent were with TIRA/ENTO, and in patients with MCL, ORR was refractory to their last prior treatment regimen before 100% with TIRA/IDELA and 64% with TIRA/ENTO. In enrolling in this study, with stable disease or PD as the best patients with other indolent NHL, the ORR was 58% with prior response. In the TIRA/ENTO group, most patients TIRA/IDELA and 67% with TIRA/ENTO. The median were relapsed rather than refractory, with 65% of FL (Q1, Q3) time to response and the median (Q1, Q3) duration Phase 1b study of tirabrutinib in combination with idelalisib or entospletinib in previously treated. . .

Table 1 Patient demographics and baseline characteristics. DLBCL FL MCL Other indolent NHL N = 56a N = 36 N = 12 N = 27

TIRA/IDELA, N 17 10 1 12 Age, median (range) years 72 (37–89) 58 (32–70) 70 (70–70) 68 (41–77) Female, n (%) 5 (29) 4 (40) 0 5 (42) Time since diagnosis, median (range) years 1.5 (0.3–7.4) 9.3 (0.3–23.0) 3.3 (3.3–3.3) 6.0 (0.0–9.4) Ann Arbor staging, n (%)a I–II 3 (18) – 00 III or IV 14 (82) – 1 (100) 11 (92) Missing 0 – 0 1 (8) Follicular lymphoma staging, n (%) Grade 1 – 0 –– Grade 2 – 7 (70) –– Grade 3a – 3 (30) –– Unknown – 0 –– ECOG performance status, n (%) 0 9 (53) 3 (30) 0 7 (58) 1 8 (47) 7 (70) 1 (100) 2 (25) ≥2 0 0 0 2 (17) Lactate dehydrogenase, U/L, median (range) 256 (157–924) 256 (176–970) 237 (237–237) 207 (72–411) Prior no. of anticancer therapies, median (range) 3.0 (1–4) 4.0 (2–6) 2.0 (2–2) 2.5 (2–5) Best response to last regimen, n (%) Complete response 2 (12) 0 0 2 (17) Partial response 5 (29) 1 (10) 1 (100) 1 (8) Stable disease 2 (12) 4 (40) 0 1 (8) Progressive disease 6 (35) 4 (40) 0 4 (33) Unknown 2 (12) 1 (10) 0 3 (25) N/A 0 0 0 1 (8) TIRA/ENTO, N 39 26 11 15 Age, median (range) years 69 (30–89) 67 (37–78) 70 (61–90) 68 (58–85) Female 12 (31) 12 (46) 0 3 (20) Time since diagnosis, median (range) years 1.7 (0.4–23.7) 6.1 (0.3–37.7) 4.6 (1.5–17.1) 6.1 (1.0–19.1) Ann Arbor staging, n (%)b I–II 7 (18) – 1 (9) 3 (20) III or IV 32 (82) – 9 (82) 10 (67) Missing 0 – 1 (9) 2 (13) Follicular lymphoma staging, n (%) Grade 1 – 3 (12) –– Grade 2 – 12 (46) –– Grade 3a – 7 (27) –– Unknown – 4 (15) –– ECOG performance status, n (%) 0 19 (49) 17 (65) 5 (46) 10 (67) 1 18 (46) 8 (31) 6 (55) 5 (33) ≥2 2 (5) 1 (4) 0 0 Lactate dehydrogenase, median (range) 250 (131–956) 222 (131–492) 208 (146–408) 156 (107–1107) Prior no. of anticancer therapies, median (range) 3.0 (1–7) 3.0 (1–12) 3.0 (2–4) 2.0 (1–6) Best response to last regimen, n (%) Complete response 7 (18) 7 (27) 4 (36) 3 (20) F. Morschhauser et al.

Table 1 (continued) DLBCL FL MCL Other indolent NHL N = 56a N = 36 N = 12 N = 27

Partial response 6 (15) 10 (39) 2 (18) 5 (33) Stable disease 12 (31) 2 (8) 3 (27) 4 (27) Progressive disease 14 (36) 5 (19) 0 1 (7) Unknown 0 2 (8) 1 (9) 2 (13) N/A 0 0 1 (9) 0 aFifty-ﬁve of the 56 DLBCL patients had non-GCB subtype, and 1 patient in the TIRA/IDELA group had GCB subtype (a protocol deviation resulting from a delayed pathology report). bFollicular lymphoma grading was missing for 4 patients.

Table 2 Incidence of treatment- TEAE summary TIRA/IDELA TIRA/ENTO emergent adverse events. N = 40 N = 91

TEAEs, n (%) 40 (100) 86 (95) TEAEs related to TIRA 31 (78) 70 (77) TEAEs leading to TIRA discontinuation 6 (15) 3 (3) TEAEs related to IDELA 31 (78) – TEAEs leading to IDELA discontinuation 7 (18) – TEAEs related to ENTO – 64 (70) TEAEs leading to ENTO discontinuation – 7 (8) SAEsa, n (%) 15 (38) 33 (36) SAEs related to TIRA 7 (18) 8 (9) SAEs related to IDELA 8 (20) – SAEs related to ENTO – 9 (10) TEAEs by MedDRA preferred termb TIRA/IDELA TIRA/ENTO Any grade Grade ≥3 Any grade Grade ≥3 Neutropenia 11 (28) 9 (23) 14 (15) 14 (15) Diarrhea 9 (23) 1 (3) 23 (25) 0 (0) Thrombocytopenia 9 (23) 5 (13) 5 (6) 3 (3) Pyrexia 8 (20) 1 (3) 13 (14) 4 (4) Cough 8 (20) 0 (0) 10 (11) 0 (0) Rash 8 (20) 1 (3) 9 (10) 1 (1) Fatigue 6 (15) 0 (0) 20 (22) 0 (0) Nausea 6 (15) 0 (0) 15 (17) 0 (0) Back pain 6 (15) 1 (3) 12 (13) 0 (0) Contusion 6 (15) 0 (0) 11 (12) 0 (0) Headache 6 (15) 1 (3) 7 (8) 0 (0) Vomiting 6 (15) 1 (3) 9 (10) 0 (0) Decreased appetite 6 (15) 0 (0) 7 (8) 0 (0) Dyspnea 6 (15) 2 (5) 10 (11) 1 (1) Rash, maculopapular 6 (15) 4 (10) 2 (2) 1 (1) Asthenia 2 (5) 0 (0) 21 (23) 1 (1) MedDRA Medical Dictionary for Regulatory Activities. aSAEs occurring in ≥2 patients in either treatment group. bTEAEs are shown according to incidence of any grade event occurring in ≥15% of patients in either treatment group. Phase 1b study of tirabrutinib in combination with idelalisib or entospletinib in previously treated. . . of response with TIRA/IDELA and TIRA/ENTO for Acknowledgements We extend our thanks to the patients and their DLBCL, FL, MCL, and other indolent NHL are shown in families. We would like to thank Jinfeng Liu, Marianna Zavo- Supplementary Table 5; Kaplan–Meier estimated duration dovskaya, and Marina Starodubtseva for support with biomarker analyses. Writing and editorial support was provided by Impact of response is shown separately for each NHL subgroup in Communication Partners, Inc. Supplementary Table 6. A ≥50% sum of the products of the longest perpendicular diameters (SPD) reduction from Author contributions FM, MJSD, HSW, AVD, SAR, RH, BL, NR, baseline occurred in 29% and 26% of DLBCL patients, in JMJ, PB, and XH designed and performed research; RH, JMJ, XH, 20% and 35% of FL patients, and in 38% and 42% of NR, and PB analyzed data; all authors participated in drafting, revis- ing, and approving the final letter. patients with other NHL subtypes (including MCL) on TIRA/IDELA and TIRA/ENTO, respectively (Supplemen- Compliance with ethical standards tary Fig. 3). PFS is shown in Supplementary Fig. 4 and MRD status in Supplementary Fig. 5. Conflict of interest FM serves on advisory boards for Roche, Celgene, The primary objective of this phase 1 study was to assess Gilead Sciences, and Epizyme, has given expert testimony for Roche, the safety and tolerability of the TIRA/IDELA and TIRA/ and has received honoraria for scientific lectures for Janssen, Celgene ENTO combinations. The AE rates were generally com- and Roche; MJSD reports research funding from Roche, Gilead Sci- ences, Astex, BioInvent, and AstraZeneca; HSW has nothing to dis- parable to those observed in previous studies of TIRA close; AVD reports research funding from Aptose Biosciences, [7, 9], IDELA [13], or ENTO [14] monotherapy in patients Verastem Oncology, AstraZeneca, Gilead Sciences, Takeda Oncology, with NHL. There were no unanticipated safety signals seen Genentech, Bayer Oncology, and Bristol Myers Squibb, and reports with either treatment combination at all doses, and the MTD consultancy for Verastem Oncology, AstraZeneca, Gilead Sciences, Genentech, TG Therapeutics, Celgene, Curis, and Seattle Genetics; LY for either combination was not reached. IDELA-associated reports consultancy for AbbVie, AstraZeneca, Gilead, Janssen, and toxicities appeared to be less frequent in our study com- Roche; DJH reports research funding from Gilead Sciences; CF has pared to what has been reported previously, possibly due to nothing to disclose; SAR reports research funding from and con- the use of lower doses [10]. In particular, no patients sultancy for Janssen, Celgene, Roche, Sunesis, Celltrion, and Astra- Zeneca, and reports speakers bureau for Janssen; JR reports research receiving TIRA/IDELA had serious TEAEs of diarrhea, funding from Takeda, reports consultancy for Takeda and Seattle colitis, or ALT/AST elevation. Genetics, reports speakers bureau for Takeda, Bristol Myers Squibb, The combination of TIRA + low-dose IDELA induced and ADC Therapeutics, and reports holding shares of GlaxoSmithK- responses in only 20% of FL patients, and the combination line and AstraZeneca; GC reports consultancy for Roche and Celgene; + KB reports consultancy for Takeda and Gilead Sciences/Kite Pharma; of TIRA ENTO yielded a 35% response rate. These ORRs AJD reports research funding from Roche, Celgene, Acerta/AstraZe- are lower than those observed in other studies of R/R FL, neca, Gilead Sciences/Kite Pharma, Karyopharma, and ADC Ther- including treatment with the approved dose of 150 mg twice apeutics, and reports consultancy for Celgene, Roche, Takeda, Acerta/ daily IDELA (54% ORR) [2, 10], copanlisib (40–55% ORR) AstraZeneca, Karyopharm, MorphoSys AG, and Janssen; SS reports research funding from Velos BioPharma, Gilead Sciences, Janssen, [3, 15], and duvelisib (42% ORR) [4]. The suboptimal Acerta Pharma, Bristol Myers Squibb, Genentech, and AstraZeneca, responses in the present study may be due to lower IDELA and reports consultancy for Janssen, Pharmacyclics, and Portola dosing. Except in the DLBCL cohort, where the 160 mg Pharmaceuticals; NR, BL, RH, XH, PB, and JMJ report employment TIRA QD dose increased IDELA plasma PK exposure with Gilead Sciences; and GS reports consultancy for AbbVie, Autolus Therapeutics, Celgene, Genmab, Gilead Sciences, relative to lower TIRA doses due to drug-drug interaction, Epizyme, Janssen, Karyopharm, Kite Pharma, Merck, MorphoSys, no further impact of TIRA on IDELA PK at lower doses, or Novartis, Roche, Servier, and Takeda, and reports speakers bureau for additional drug-drug interactions were observed in the study AbbVie, Amgen, Celgene, Gilead Sciences, Janssen, Kite Pharma, [12]. Consistent with a previous IDELA dose-ranging study MorphoSys, Novartis, Roche, Servier, and Takeda. [13], outcomes in DLBCL patients treated with TIRA/ Publisher’s note Springer Nature remains neutral with regard to IDELA (N = 17) suggest that reduced IDELA exposure had jurisdictional claims in published maps and institutional affiliations. a detrimental impact on efficacy. The overall hypothesis for this study was to explore Open Access This article is licensed under a Creative Commons whether combining different BCR-targeted agents at lower Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as doses than their respective doses in monotherapy offers a long as you give appropriate credit to the original author(s) and the meaningful strategy to increase tolerability while preserving source, provide a link to the Creative Commons license, and indicate if or improving efficacy. Based on the results of this study, we changes were made. The images or other third party material in this conclude that while the explored combinations of TIRA/ article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not IDELA and TIRA/ENTO were overall well tolerated, there included in the article’s Creative Commons license and your intended was no meaningful efficacy advantage to be gained with this use is not permitted by statutory regulation or exceeds the permitted approach. It is possible that any advantage achieved in use, you will need to obtain permission directly from the copyright safety through lower doses may in fact have compromised holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. efficacy in this study. F. Morschhauser et al.

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